hepatic autoimmune overlap syndrome

Definition: Some patients present with overlapping features between disorders within the spectrum of autoimmune liver diseases (i.e. autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC)) and are commonly classified as having an "overlap syndrome". Autoimmune hepatitis (AIH), primary biliary cirrhosis, and primary sclerosing cholangitis are the three major autoimmune diseases affecting the liver.

Standardized definitions of "overlap syndromes" are lacking.

Autoimmune hepatitis (AIH)

Of these three, AIH is the most typical autoimmune disease being characterized by a T-cell-rich infiltrate, raised circulating γ-globulins, autoantibodies, HLA associations, and links with other autoimmune diseases. It is the only one, of the three diseases, that responds well to immunosuppressive therapy. AIH is caused by dysregulation of immunoregulatory networks and the consequent emergence of autoreactive T cells that orchestrate a progressive destruction of hepatocytes leading untreated to liver failure. T cells play a major role in the immunopathogenesis, and both CD4(+) and CD8(+) T cells are involved together with effector responses mediated by NK cells, γδ T cells, and macrophages.

A number of triggering factors have been proposed including viruses, xenobiotics, and drugs, but none have been conclusively shown to be involved in pathogenesis.

The IAIHG scoring system

The IAIHG scoring system for diagnosis of AIH has been widely used to diagnose "overlap syndromes", but was not intended for such use and has not proven to be an efficient tool for this purpose.

Some patients with overlapping features between a cholestatic and hepatitic disorder appear to benefit from treatment with a combination of ursodeoxycholic acid and immunosuppressants, but this strategy is not evidence-based, and it seems unjustified to define new diagnostic groups in this regard.

The IAIHG suggests that patients with autoimmune liver disease should be categorized according to the predominating feature(s) as AIH, PBC, and PSC/small duct PSC, respectively, and that those with overlapping features are not considered as being distinct diagnostic entities.

The IAIHG scoring system should not be used to establish subgroups of patients.

Patients with PBC and PSC with features of AIH should be considered for immunosuppressive treatment.

Physiopathology

Overlap syndromes are classified as autoimmune liver diseases that are difficult to classify within a single diagnostic category, such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), or AIH, because they have biochemical, immunological, clinical, or histological features suggestive of more than 1 disease process.

The common forms seen are PBC with features of AIH and biliary features suggestive of PSC in AIH.

They usually occur at the same time (true overlap syndromes), but in some cases, patients present with features of one disease and subsequently develop features of the other, sometimes after intervals of several years (sequential overlap syndromes).

Sequential syndromes involving PBC and AIH typically present with features of PBC first, whereas in those involving PSC and AIH, features of AIH usually occur first.

In the context of PBC, the “overlap syndrome” probably represents one end of a spectrum of immune-mediated injury in which damage to hepatocytes is more prominent and takes the form of interface hepatitis.

Even in a biliary disease such as PBC, a degree of parenchymal inflammation is seen in the form of interface or lobular hepatitis.

This could reflect antigen-specific T-cell destruction of hepatocytes, but as both the antigen and the cellular target in PBC are so well characterized, this seems unlikely.

Hepatic inflammation may therefore be mediated by bystander mechanisms that cause collateral damage to hepatocytes.

Collateral hepatocyte damage can result in the release of intracellular antigens and the development of autoantibodies.

This categorization is of more than academic importance because it has implications for outcome and treatment.

There is now good evidence that patients with PBC associated with florid interface hepatitis respond to immunosuppressive therapy whereas those in whom the biliary features predominate do not and should be treated with ursodeoxycholic acid alone.

Why hepatitis should be more steroid sensitive than biliary inflammation is not clear. One possibility is that biliary epithelial cells maintain effector cell survival by providing anti-apoptotic signals through cell-surface integrin ligands such as VCAM-1 and by secreting cytokines.

Both AIH and PSC can be associated with inflammatory bowel disease (IBD), and there is evidence that they can occur sequentially in patients who present with typical AIH subsequently developing PSC.

Evidence suggests that the liver disease is driven by the recruitment of effector lymphocytes that were activated in the gut.

When lymphocytes are activated in gut-associated lymphoid tissues, they are not only programmed to respond to antigen but are also imprinted with a homing phenotype that directs their subsequent trafficking back to the gut.

After antigen clearance, long-lived memory cells remain that retain gut tropism and thereby provide immune surveillance against the same pathogen entering the gut in the future.

The molecular basis of this tissue-specific homing has recently been elucidated and involves interactions with tissue-specific adhesion molecules and chemokines on the endothelium lining the vessels in the target tissue, which are recognized by lymphocytes with appropriate receptors.

Endothelium in the gut expresses a unique adhesion molecule called mucosal addressin cell adhesion molecule-1 (MADCAM-1), which is absent from other vascular beds, and a unique chemokine CCL25, which is restricted to the small bowel.

Activation of lymphocytes in the gut imprints them with the receptors for these gut-specific molecules: the integrin α4β7 and the chemokine receptor CCR9, respectively.

Twenty percent of the T cells infiltrating the liver in AIH/PSC complicating IBD are α4β7+CCR9+ and thus of gut origin, whereas these cells are found at very low frequencies in other liver diseases.

Furthermore, these memory/effector T cells secrete IFN-γ, suggesting that they are effector cells capable of promoting liver inflammation.

Both MADCAM-1 and CCL25, which are absent from normal liver, are present on hepatic endothelium in liver diseases associated with IBD, providing a mechanism for recruiting these cells.

Thus, some mucosal lymphocytes can bind liver endothelium, allowing them to recirculate between the liver and the gut to provide immune surveillance across both sites.

If these cells are activated by cross-reactive liver antigens or gut antigens that have entered through the portal circulation, this can lead to their local expansion and the establishment of chronic inflammation in the form of AIH or PSC.

The link between AIH and PSC is further supported by the observations that they can occur together, or sequentially, particularly in children. The King’s liver unit reported the presence of histological and/or radiological biliary features compatible with PSC in 50% of children who otherwise fulfilled criteria for AIH.

Czaja and Carpenter reported that 20 of 84 adult patients with AIH had biliary changes on liver biopsy in the absence of anti-mitochondrial autoantibodies.

In other respects, they behaved like AIH and responded to immunosuppressive therapy.

Current evidence suggests that PSC may be preceded in some patients by AIH, particularly in children and adolescents.

The pediatric patients usually respond to corticosteroids, unlike patients with classical PSC, although as the biliary features progress, response to immunosuppression may be lost.

The reasons for the relative treatment resistance of AIH with biliary features may involve the same mechanisms discussed earlier under PBC.

All this evidence suggests that in some patients, particularly those with IBD, autoimmune sclerosing cholangitis and AIH may be part of the same disease process, with AIH progressing to a biliary syndrome resembling PSC.

The implications from these findings are that AIH/PSC overlap is more common than previously suspected and biliary features should be sought carefully in patients with AIH both histologically and, if indicated, MR cholangiography.

This is particularly true if an elevated alkaline phosphatase level is noted. Addition of ursodeoxycholic acid rather than an increase in immunosuppression may improve biochemistry in such patients.

Interestingly, patients with overt AIH who test positive for anti-mitochondrial antibodies (AMAs) at initial presentation and are treated with corticosteroid therapy have shown no clinical or histological evidence of PBC despite the continued detection of AMAs over a long-term follow-up.

References

 Autoimmune hepatitis: new paradigms in the pathogenesis, diagnosis, and management. Oo YH, Hubscher SG, Adams DH. Hepatol Int. 2010 May 19;4(2):475-93. PMID: 20827405 (Free)